The effect of portal hepatotrophic factors on liver morphology, function, and capacity for regeneration was investigated. The hepatocyte atrophy and ultrastructural disorganization caused by portacaval shunt was duplicated in dogs by evisceration. Total non-hepatic splanchnic evisceration abolished hepatic regeneration. The dependence of the liver upon portal flow was at least in part dependent upon endogenous hormones delivered from the viscera and carried on first pass to the liver by concentration. The regenerative fragments of dog livers after subtotal hepatectomy developed a stimulatory factor which caused hepatocyte proliferation and which prevented atrophy in test dogs submitted to Eck fistula. There are many clinical implications to the foregoing findings.